Cleft lip with or without cleft palate (CL(P)) is the most common birth defect in humans. The majority are non-syndromic. Many CL(P) cases are sporadic, but autosomal dominant inheritance with incomplete penetrance also has been reported. Recent studies suggest that as few as 4 loci are responsible for some part of CL(P). At least one type of CL(P) appears to be the result of a mutation at a locus on the long arm of chromosome 4. The proposed hypothesis is that one or more major genes associated with CL(P) can be identified and localized to a chromosome by the use of standard PCR markers. We have identified one such locus at 4q. Furthermore, we wish to test the available microsatellite markers on newly ascertained families to refine the localization of the gene. These families are multiplex, with at least 3 affecteds in each family. Complex syndromic cases will be excluded from analysis. All the markers found to be polymorphic will be mapped in our new CL(P) families to determine if they are within the region of interest and, if so, used to refine the region of localization to 0.5-2.0 centimorgans. In order to increase the density of polymorphic probes in the region of interest, a Yeast Artificial Chromosome (YAC) library based walking will be made. The region specific YACs will be used to isolate polymorphic markers. Linkage analysis of DNA markers will be performed by using the program, LINKAGE, version 5.03. In conclusion, the localization of a CL(P) gene could eventually open the possibility of cloning the CL(P) susceptible gene and finally such results will be useful for diagnosis and counseling.